tbuckley/cabot-search huggingface dataset:
Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity
Authors: Lihui Liu, Sini Li, Yan Qu, Hua Bai, Xiangyu Pan, Jian Wang, Zhijie Wang, Jianchun Duan, Jia Zhong, Rui Wan, Kailun Fei, Jiachen Xu, Li Yuan, Chao Wang, Pei Xue, Xue Zhang, Zixiao Ma, Jie Wang
Journal: Cell Reports Medicine (2023)

Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy efficacy. However, strategies for characterizing the TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1α (ERO1A) mediates an immune-suppressive TME and attenuates the response to PD-1 blockade. Ablation of ERO1A in tumor cells substantially incites anti-tumor T cell immunity and promotes the efficacy of aPD-1 in therapeutic models. Single-cell RNA-sequencing analyses confirm that ERO1A correlates with immunosuppression and dysfunction of CD8+ T cells along anti-PD-1 treatment. In human lung cancer, high ERO1A expression is associated with a higher risk of recurrence following neoadjuvant immunotherapy. Mechanistically, ERO1A ablation impairs the balance between IRE1α and PERK signaling activities and induces lethal unfolded protein responses in tumor cells undergoing endoplasmic reticulum stress, thereby enhancing anti-tumor immunity via immunogenic cell death. These findings reveal how tumor ERO1A induces immunosuppression, highlighting its potential as a therapeutic target for cancer immunotherapy.
Development of an automated estimation of foot process width using deep learning in kidney biopsies from patients with Fabry, minimal change, and diabetic kidney diseases
Authors: David Smerkous, Michael Mauer, Camilla Tøndel, Einar Svarstad, Marie-Claire Gubler, Robert G. Nelson, João-Paulo Oliveira, Forough Sargolzaeiaval, Behzad Najafian
Journal: Kidney International (2023)
Advanced optical imaging reveals preferred spatial orientation of podocyte processes along the axis of glomerular capillaries
Authors: David Unnersjö-Jess, Amer Ramdedovic, Linus Butt, Ingo Plagmann, Martin Höhne, Agnes Hackl, Hjalmar Brismar, Hans Blom, Bernhard Schermer, Thomas Benzing
Journal: Kidney International (2023)

Mammalian kidneys filter enormous volumes of water and small solutes, a filtration driven by the hydrostatic pressure in glomerular capillaries, which is considerably higher than in most other tissues. Interdigitating cellular processes of podocytes form the slits for fluid filtration connected by the membrane-like slit diaphragm cell junction containing a mechanosensitive ion channel complex and allow filtration while counteracting hydrostatic pressure. Several previous publications speculated that podocyte processes may display a preferable orientation on glomerular capillaries instead of a random distribution. However, for decades, the controversy over spatially oriented filtration slits could not be resolved due to technical limitations of imaging technologies. Here, we used advanced high-resolution, three-dimensional microscopy with high data throughput to assess spatial orientation of podocyte processes and filtration slits quantitatively. Filtration-slit-generating secondary processes preferentially align along the capillaries' longitudinal axis while primary processes are preferably perpendicular to the longitudinal direction. This preferential orientation required maturation in development of the mice but was lost in mice with kidney disease due to treatment with nephrotoxic serum or with underlying heterologous mutations in the podocyte foot process protein podocin. Thus, the observation that podocytes maintain a preferred spatial orientation of their processes on glomerular capillaries goes well in line with the role of podocyte foot processes as mechanical buttresses to counteract mechanical forces resulting from pressurized capillaries. Future studies are needed to establish how podocytes establish and maintain their orientation and why orientation is lost under pathological conditions.
Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE<sup>-/-</sup>mice
Authors: Peng Xiang, Qingqiu Chen, Le Chen, Jin Lei, Zhiyi Yuan, Hui Hu, Yining Lu, Xianmin Wang, Tingting Wang, Ruihong Yu, Wanping Zhang, Jun Zhang, Chao Yu, Limei Ma
Journal: Theranostics (2023)

Background: Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Methods: Here, we mimicked an animal model in ApoE-/- mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. Results: We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1β, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in ApoE-/- mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Conclusions: Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.
<i>FN1</i> mRNA 3'-UTR supersedes traditional fibronectin 1 in facilitating the invasion and metastasis of gastric cancer through the <i>FN1</i> 3'-UTR-let-7i-5p-THBS1 axis
Authors: Siwei Pan, Jiaming Zhu, Pengfei Liu, Qiaochu Wei, Siyu Zhang, Wen An, Yuxin Tong, Zhenguo Cheng, Funan Liu
Journal: Theranostics (2023)

Background: Current clinical treatments for gastric cancer (GC), particularly advanced GC, lack infallible therapeutic targets.The 3′-untranslated region (3′-UTR) has attracted increasing attention as a drug target.Methods: In vitro and in vivo experiments were conducted to determine the function of FN1 3′-UTR and FN1 protein in invasion and metastasis.RNA pull-down assay and high-throughput sequencing were used to screen the factors regulated by FN1 3′-UTR and construct the regulatory network.Western blotting and polymerase chain reaction were used to examine the correlation of intermolecular expression levels.RNA-binding protein immunoprecipitation was used to verify the correlation between FN1 3′-UTR and target mRNAs. Results:The FN1 3′-UTR may have stronger prognostic implications than the FN1 protein in GC patients.Upregulation of FN1 3′-UTR significantly promoted the invasive and metastatic abilities of GC cells to a greater extent than FN1 protein in vitro and in vivo.A novel regulatory network was constructed based on the FN1 3′-UTR-let-7i-5p-THBS1 axis, wherein FN1 3′-UTR displayed stronger oncogenic effects than the FN1 protein.Conclusions: FN1 3′-UTR may be a better therapeutic target for constructing targeted drugs in GC than the FN1 protein.
Targeting cullin neddylation for cancer and fibrotic diseases
Authors: Zhang-Xu He, Wei-guang Yang, Dan Zengyangzong, Ge Gao, Qian Zhang, Hong-Min Liu, Wen Zhao, Li-Ying Ma
Journal: Theranostics (2023)

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.
Exosomal transfer leads to chemoresistance through oxidative phosphorylation-mediated stemness phenotype in colorectal cancer
Authors: Jinhai Deng, Teng Pan, Chunxin Lv, Lulu Cao, Lifeng Li, Xingang Zhou, Gang Li, Huanxin Li, Jose M Vicencio, Yihan Xu, Fengxiang Wei, Yazhou Wang, Zaoqu Liu, Guanglin Zhou, Mingzhu Yin
Journal: Theranostics (2023)

Background: Recently years have seen the increasing evidence identifying that OXPHOS is involved in different processes of tumor progression and metastasis and has been proposed to be a potential therapeutical target for cancer treatment. However, the exploration in oxidative phosphorylation-mediated chemoresistance is still scarce. In our study, we identify exosomal transfer leads to chemoresistance by reprogramming metabolic phenotype in recipient cells. Methods: RNA sequencing analysis was used to screen altered targets mediating exosome transfer-induced chemoresistance. Seahorse assay allowed us to measure mitochondrial respiration. Stemness was measured by spheroids formation assay. Serum exosomes were isolated for circ_0001610 quantification. Results: The induced oxidative phosphorylation leads to more stem-like properties, which is dependent on the transfer of exosomal circ_0001610. Exosome transfer results in the removal of miR-30e-5p-mediated suppression of PGC-1a, a master of mitochondrial biogenesis and function. Consequently, increased PGC-1a reshapes cellular metabolism towards oxidative phosphorylation, leading to chemoresistance. Inhibition of OXPHOS or exosomal si-circ_0001610 increases the sensitivity of chemotherapy by decreasing cell stemness in vitro and in vivo. Conclusion: Our data suggests that exosomal circ_0001610-induced OXPHOS plays an important role in chemoresistance and supports a therapeutical potential of circ_0001610 inhibitors in the treatment of oxaliplatin-resistant colorectal cancer by manipulating cell stemness.
Polymer theranostics with multiple stimuli-based activation of photodynamic therapy and tumor imaging
Authors: Marina Rodrigues Tavares, Rayhanul Islam, Vladimír Šubr, Steffen Hackbarth, Shanghui Gao, Kai Yang, Volodymyr Lobaz, Jun Fang, Tomáš Etrych
Journal: Theranostics (2023)

Background: Efficient theranostic strategies concurrently bring and use both the therapeutic and diagnostic features, serving as a cutting-edge tool to combat advanced cancers.Goals of the Investigation: Here, we develop stimuli-sensitive theranostics consisting of tailored copolymers forming micellar conjugates carrying pyropheophorbide-a (PyF) attached by pH-sensitive hydrazone bonds, thus enabling the tumor microenvironment-sensitive activation of the photodynamic therapy (PDT) effect, fluorescence or phosphorescence. Results:The nanomedicines show superior anti-tumor PDT efficacy and huge tumor-imaging potential, while reducing their accumulation, and potentially side effects, in the liver and spleen.The developed theranostics exhibit clear selective tumor accumulation at high levels in the mouse sarcoma S180 tumor model with almost no PyF found in the healthy tissues after 48 h.Once in the tumor, illumination at λexc = 420 nm reaches the therapeutic effect due to the 1 O2 generation.Indeed, an almost complete inhibition of tumor growth is observed up to 18 days after the treatment. Conclusion:The clear benefit of the specific PyF release and activation in the acidic tumor environment for the targeted delivery and tissue distribution dynamics was proved.Conjugates carrying pyropheophorbide-a (PyF) attached by pH-sensitive hydrazone bonds showed their excellent antitumor PDT effect and its applicability as advanced theranostics at very low dose of PyF.
Targeted elimination of senescent cells by engineered extracellular vesicles attenuates atherosclerosis in ApoE<sup>-/-</sup> mice with minimal side effects
Authors: Liang Zhang, Chen Wang, Wei Hu, Te Bu, Wenqi Sun, Tian Zhou, Shuo Qiu, Mengying Wei, Helin Xing, Zhelong Li, Guodong Yang, Lijun Yuan
Journal: Theranostics (2023)

Senescent cells in plaques emerge as a detrimental factor for atherosclerosis (AS), for which targeted senolysis might be a promising therapeutic strategy. The development of safe and efficient senolytics for senescent cell eradication by targeted delivery is greatly needed.
Detection of lineage-reprogramming efficiency of tumor cells in a 3D-printed liver-on-a-chip model
Authors: Zuyan Lu, Xiangwan Miao, Qianqian Song, Huifen Ding, Shiny Amala Priya Rajan, Aleksander Skardal, Konstantinos I. Votanopoulos, Kerong Dai, Weixin Zhao, Baisong Lu, Anthony Atala
Journal: Theranostics (2023)

Background: The liver metastasis accompanied with the loss of liver function is one of the most common complications in patients with triple-negative breast cancers (TNBC). Lineage reprogramming, as a technique direct inducing the functional cell types from one lineage to another lineage without passing through an intermediate pluripotent stage, is promising in changing cell fates and overcoming the limitations of primary cells. However, most reprogramming techniques are derived from human fibroblasts, and whether cancer cells can be reversed into hepatocytes remains elusive. Methods: Herein, we simplify preparation of reprogramming reagents by expressing six transcriptional factors (HNF4A, FOXA2, FOXA3, ATF5, PROX1, and HNF1) from two lentiviral vectors, each expressing three factors. Then the virus was transduced into MDA-MB-231 cells to generated human induced hepatocyte-like cells (hiHeps) and single-cell sequencing was used to analyze the fate for the cells after reprogramming. Furthermore, we constructed a Liver-on-a-chip (LOC) model by bioprinting the Gelatin Methacryloyl hydrogel loaded with hepatocyte extracellular vesicles (GelMA-EV) bioink onto the microfluidic chip to assess the metastasis behavior of the reprogrammed TNBC cells under the 3D liver microenvironment in vitro. Results: The combination of the genes HNF4A, FOXA2, FOXA3, ATF5, PROX1 and HNF1A could reprogram MDA-MB-231 tumor cells into human-induced hepatocytes (hiHeps), limiting metastasis of these cells. Single-cell sequencing analysis showed that the oncogenes were significantly inhibited while the liver-specific genes were activated after lineage reprogramming. Finally, the constructed LOC model showed that the hepatic phenotypes of the reprogrammed cells could be observed, and the metastasis of embedded cancer cells could be inhibited under the liver microenvironment. Conclusion: Our findings demonstrate that reprogramming could be a promising method to produce hepatocytes and treat TNBC liver metastasis. And the LOC model could intimate the 3D liver microenvironment and assess the behavior of the reprogrammed TNBC cells.
Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy
Authors: Minjee Kim, Hyeyoung Kim, Bu-Gyeong Kang, Jooyoung Lee, Taegun Kim, Hwanho Lee, Jane Jung, Myung Joon Oh, Seungyoon Seo, Myung-Jeom Ryu, Yeojin Sung, Yunji Lee, Jeonghun Yeom, Gyoonhee Han, Sun-Shin Cha, Hosung Jung, Hyun Seok Kim
Journal: Theranostics (2023)

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.
Application of Lung-Targeted Lipid Nanoparticle-delivered mRNA of soluble PD-L1 via SORT Technology in Acute Respiratory Distress Syndrome
Authors: Han Sun, Yu Zhang, Jiahui Wang, Juncheng Su, Dejian Zhou, Xiang Yu, Yingjie Xu, Wen Yang
Journal: Theranostics (2023)

Rationale: Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by excessive immune response usually due to lung inflammation. Local immunosuppression is crucial for effective ARDS treatment. However, current methods are limited in their ability to target the lungs specifically. Methods: This study utilized lung-targeted lipid nanoparticles (LNPs) with 1,2-dioleoyl-3-trimethylammonium-propane (termed DOTAP-LNPs) to encapsulate chemically modified soluble programmed death ligand-1 (sPD-L1) mRNA and examined its physiological characteristics and therapeutic efficacy. A comparative analysis was performed between sPD-L1 mRNA delivered by DOTAP-LNPs, sPD-L1 mRNA delivered by regular LNPs (MC3-LNPs), and PD-L1-Fc recombinant protein administered systemically. Additionally, the survival rate of ARDS mice treated with different drugs was assessed. Results: Administration of sPD-L1 mRNA-LNPs to ARDS model mice significantly reduced leukocyte chemotaxis and protein accumulation in lung tissue, along with a decrease in pulmonary edema. Notably, in situ intervention using sPD-L1 mRNA-DOTAP-LNPs exhibited superior therapeutic effects compared to PD-L1-Fc recombinant protein and sPD-L1 mRNA encapsulated in MC3-LNPs. Importantly, treatment with sPD-L1 mRNA-DOTAP-LNPs improved the survival rate of ARDS model mice. Conclusion: This study demonstrates the feasibility of utilizing stable and reliable mRNA to express the immunosuppressive molecule sPD-L1 specifically in the lungs. The findings provide proof of concept for localized nanoparticle delivery and offer a novel therapeutic strategy for treating acute inflammation in ARDS.
E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma
Authors: YanLan Li, Lingbo Bao, Hong Zheng, Mingying Geng, TianYi Chen, Xiaoyan Dai, He Xiao, Lujie Yang, Chengyi Mao, Yuan Qiu, Yu Xu, Dong Wang, Meng Xia Li, Qian Chen
Journal: Theranostics (2023)

Background: Elucidation of the mechanism of ubiquitation has led to novel ways to treat glioblastoma (GBM).A tripartite motif (TRIM) protein mediates a reversible, stringent ubiquitation which is closely related to glioma malignancy.This study intends to screen the most vital and abnormal regulating component of the tripartite motif protein and to explore its underlying mechanisms.Methods: TRIM21 is identified as an important oncogene that accelerates the progression of glioma cell through database in a multidimensional way and this is confirmed in human samples and cells.Tandem Mass Tags (TMT) and MS analysis are performed to discover the substrates of TRIM21.The underlying mechanisms are further investigated by CO-IP, luciferase reporter assays and gain and loss of function assays.In vivo treatment with siRNA is applied to evaluate the therapeutic significance of TRIM21.Result: We screened a panel of TRIM proteins and identified TRIM21, a E3 ubiquitin-protein ligase and autoantigen, as well as a prognostic biomarker for GBM.Functionally, high expression of wild-type TRIM21 accelerates tumor progression in vitro and in vivo, whereas TRIM21 mutants, including one with a critical RING-finger deletion, do not.Mechanistically, TRIM21 stimulates K63-linked ubiquitination and subcellular translocation of active β-catenin from the cytoplasm to the nucleus.Moreover, TRIM21 forms a complex with the β-catenin upstream regulator, TIF1γ, in the nucleus and accelerated its degradation by inducing K48-linked ubiquitination at K5 site, consequently increasing further nuclear β-catenin presence.Endogenous TRIM21 levels are found to be inversely correlated with TIF1γ but positively correlated with β-catenin in glioma tissue microarray experiments.Furthermore, direct injection of TRIM21 small interfering RNA (siRNA) into U87 cell-derived tumors (in vivo treatment with siRNA) is proved to inhibit tumor growth in nude mice.Conclusion: This work suggests that TRIM21/TIF1γ/β-catenin axis is involved in the progression of human GBM.TRIM21 is a promising therapeutic and prognostic biomarker for glioma with hyperactive β-catenin.